Bottom Line:
Pathways and biological processes associated with differentially regulated genes were mainly those thought to be involved in fear-related behavioral responses and neuronal signaling.Signaling pathways associated with PTSD-comorbid conditions, such as diabetes, metabolic disorder, inflammation and cardiac infarction, were also significantly enriched.Our data suggests activations of behavioral responses associated with anxiety disorders as well as inhibition of neuronal signaling pathways important for neurogenesis, cognition and extinction of fear memory.

Results: Pathways and biological processes associated with differentially regulated genes were mainly those thought to be involved in fear-related behavioral responses and neuronal signaling. Expression-based assessments of activation patterns showed increased activations of pathways related to anxiety disorders (hyperactivity and fear responses), impaired cognition, mood disorders, circadian rhythm disruption, and impaired territorial and aggressive behaviors. In amygdala, activations of these pathways were more pronounced at earlier time-points, with some attenuation after longer rest periods. In hippocampus and medial prefrontal cortex, activation patterns were observed at later time points. Signaling pathways associated with PTSD-comorbid conditions, such as diabetes, metabolic disorder, inflammation and cardiac infarction, were also significantly enriched. In contrast, signaling processes related to neurogenesis and synaptic plasticity were inhibited.

Conclusions: Our data suggests activations of behavioral responses associated with anxiety disorders as well as inhibition of neuronal signaling pathways important for neurogenesis, cognition and extinction of fear memory. These pathways along with comorbid-related signaling pathways indicate the pervasive and multisystem effects of aggressor exposure in mice, potentially mirroring the pathologic conditions of PTSD patients.

Fig8: Transcripts – brain-regions interactome for transcripts that passed p-value less than 0.01 and fold change greater than 2.0 in Agg-E groups compared to control groups (across time points).

Mentions:
We constructed transcript – brain-region interactome using transcripts that passed p-value less than 0.01 and more than 2 fold across brain regions and time points (Figure 8). Persistent with what we observed with whole set of DEGs, the expression patterns of AY and HC were reversed for the early (5d1d) and for the late (10d42d) time points for transcripts filtered with stricter cut offs. This corroborates our suggested activation and inhibition of behavioral responses across time points among AY, HC and MPFC. Transcripts at early time point (5d1d) from AY were largely induced whereas they were suppressed in HC (Figure 8, Additional file 1: Figure S9). On the other hand, transcripts at later time point (10d42h) showed reversed expression pattern between AY and HC (Figure 8, Additional file 1: Figure S12), which is again consistent with our expression based prediction analyses. At the transcript level, there were not many shared DEGs among combinations of brain-regions and time points. But there were more overlaps at the pathway and process levels (Additional file 1: Figures S9-S18).Figure 8

Fig8: Transcripts – brain-regions interactome for transcripts that passed p-value less than 0.01 and fold change greater than 2.0 in Agg-E groups compared to control groups (across time points).

Mentions:
We constructed transcript – brain-region interactome using transcripts that passed p-value less than 0.01 and more than 2 fold across brain regions and time points (Figure 8). Persistent with what we observed with whole set of DEGs, the expression patterns of AY and HC were reversed for the early (5d1d) and for the late (10d42d) time points for transcripts filtered with stricter cut offs. This corroborates our suggested activation and inhibition of behavioral responses across time points among AY, HC and MPFC. Transcripts at early time point (5d1d) from AY were largely induced whereas they were suppressed in HC (Figure 8, Additional file 1: Figure S9). On the other hand, transcripts at later time point (10d42h) showed reversed expression pattern between AY and HC (Figure 8, Additional file 1: Figure S12), which is again consistent with our expression based prediction analyses. At the transcript level, there were not many shared DEGs among combinations of brain-regions and time points. But there were more overlaps at the pathway and process levels (Additional file 1: Figures S9-S18).Figure 8

Bottom Line:
Pathways and biological processes associated with differentially regulated genes were mainly those thought to be involved in fear-related behavioral responses and neuronal signaling.Signaling pathways associated with PTSD-comorbid conditions, such as diabetes, metabolic disorder, inflammation and cardiac infarction, were also significantly enriched.Our data suggests activations of behavioral responses associated with anxiety disorders as well as inhibition of neuronal signaling pathways important for neurogenesis, cognition and extinction of fear memory.

Results: Pathways and biological processes associated with differentially regulated genes were mainly those thought to be involved in fear-related behavioral responses and neuronal signaling. Expression-based assessments of activation patterns showed increased activations of pathways related to anxiety disorders (hyperactivity and fear responses), impaired cognition, mood disorders, circadian rhythm disruption, and impaired territorial and aggressive behaviors. In amygdala, activations of these pathways were more pronounced at earlier time-points, with some attenuation after longer rest periods. In hippocampus and medial prefrontal cortex, activation patterns were observed at later time points. Signaling pathways associated with PTSD-comorbid conditions, such as diabetes, metabolic disorder, inflammation and cardiac infarction, were also significantly enriched. In contrast, signaling processes related to neurogenesis and synaptic plasticity were inhibited.

Conclusions: Our data suggests activations of behavioral responses associated with anxiety disorders as well as inhibition of neuronal signaling pathways important for neurogenesis, cognition and extinction of fear memory. These pathways along with comorbid-related signaling pathways indicate the pervasive and multisystem effects of aggressor exposure in mice, potentially mirroring the pathologic conditions of PTSD patients.